Cyclooxygenase-2 inhibition

ABSTRACT

Selective inhibitors of cyclooxygenase-2 are used to treat liver disease and in combination with anti-viral drugs to treat virus-caused liver disorders. Selective inhibitors of cyclooxygenase-2 which also inhibit the synthesis of cyclooxygenase-2 improve over the efficacy of conventional selective inhibitors of cyclooxygenase-2 in the treatment of inflammatory conditions, Alzheimer&#39;s disease and cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 371 of PCT/US98/25206 filed Dec. 7, 1998 whichclaims the benefit of U.S. Provisional Application No. 60/069,955 filedDec. 17, 1997.

TECHNICAL FIELD

One invention herein is directed to an expansion of the use of selectiveinhibitors of cyclooxygenase-2. A different invention herein is directedto cyclooxygenase-2 inhibitors with antioxidant properties.

BACKGROUND OF THE INVENTION

Substantial research is currently being carried out to develop selectiveinhibitors of cyclooxygenase-2, i.e., agents which selectively inhibitcyclooxygenase-2 in preference to cyclooxygenase-1, so as to obtain theanti-inflammatory effect of cyclooxygenase-2 inhibition without thegastrointestinal side effects, e.g., peptic ulcer disease, that occurwhen cyclooxygenase-1 is also inhibited. Commonly used nonsteroidalanti-inflammatory drugs inhibit both cyclooxygenase-2 andcyclooxygenase-1, and the aforementioned side effects detract from theirusefulness.

The focus of the research has been on synthesis of new compoundsproviding selective inhibition of cyclooxygenase-2 for use for treatingcertain inflammatory conditions, especially arthritis. The focus has notbeen on developing new methods of treatment, i.e., on treatingconditions not heretofore considered as appropriately treatable withcyclooxygenase-2 inhibitors. The focus has not been on developingcompounds with desirable functions in addition to enzyme inhibition.

Heretofore, it was considered that cyclooxygenase inhibitors could causeliver injury and for that reason liver disease was not considered as oneof the conditions that was treatable by selective inhibitors ofcyclooxygenase-2.

SUMMARY OF THE INVENTION

One embodiment herein, sometimes referred to hereinafter as the firstembodiment herein, is directed to a method of treating a patient withliver disease comprising administering to said patient acyclooxygenase-2 inhibiting amount of a selective inhibitor ofcyclooxygenase-2. Most liver diseases are treated with minimal success.There is no effective treatment for alcoholic liver injury. Althoughchronic hepatitis C affects millions of individuals, interferon therapyis effective in eradicating the virus in a relatively small percentageof patients, and in patients where the virus is not eradicated, thecondition can progress to cirrhosis requiring liver transplantation.Invention in the method of treatment herein resides in the realizationthat the anti-inflammatory properties of selective cyclooxygenase-2inhibitors will provide a net benefit in treating liver disease and theonly effective treatment in many cases. This represents a major advance.Even considering just the ability to delay the progression of cirrhosis,the aforedescribed treatment method has enormous clinical implications.

A second embodiment herein is directed to a method of treating a patientwith a virus-caused liver disease comprising administering to saidpatient a cyclooxygenase-2 inhibiting amount of a selective inhibitor ofcyclooxygenase-2 and therapeutic amount(s) of anti-viral drug(s) wherethe cyclooxygenase-2 inhibitor is an adjunct to anti-viral therapy toincrease the effectiveness thereof. In this embodiment, the treatmentwith a selective inhibitor of cyclooxygenase-2 is considered to cause adecrease in the synthesis of immunosuppressive eicosanoids, therebyaugmenting anti-viral therapy.

A third embodiment herein is directed to selective inhibitor ofcyclooxygenase-2 which directly inhibits the enzyme cyclooxygenase-2 andwhich also inhibits the synthesis of the cyclooxygenase-2 protein andwhich has antioxidant properties.

The term “selective inhibitor of cyclooxygenase-2” is used herein tomean compound which selectively inhibits cyclooxygenase-2 in preferenceto cyclooxygenase-1 and particularly compound for which the ratio of theIC₅₀ concentration (concentration inhibiting 50% of activity) forcyclooxygenase-1 to the IC₅₀ concentration for cyclooxygenase-2 isgreater than 1. Such ratio is readily determined by assaying forcyclooxygenase-2 activity and assaying for cyclooxygenase-1 activity bythe methods set forth at column 39, line 55—column 40, line 36 of Talleyet al. U.S. Pat. No. 5,633,272, which is incorporated herein byreference, and from the resulting data obtaining a ratio of IC₅₀s.

DETAILED DESCRIPTION

We turn now to the embodiment herein directed to a method of treating apatient with a liver disease comprising administering to said patient acyclooxygenase-2 inhibiting amount of a selective inhibitor ofcyclooxygenase-2.

The liver diseases treated herein comprise inflammatory liver disordersand include, for example, chronic viral hepatitis B, chronic viralhepatitis C, alcoholic liver injury, primary biliary cirrhosis,autoimmune hepatitis, nonalcoholic steatohepatitis, and liver transplantrejection.

The selective inhibitors of cyclooxygenase-2 are preferably those wherethe ratio of the IC₅₀ concentration for cyclooxygenase-1 to the IC₅₀concentration for cyclooxygenase-2 is 5 or more, very preferably 100 ormore.

Selective inhibitors of cyclooxygenase-2 include the followingcompounds:

-   (1)    4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (2)    4-[5-(4-Bromophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (3)    4-[5-(3-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (4)    4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (5)    4-[5-(2-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (6)    4-[5-(4-Trifluoromethylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (7)    4-[5-(4-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (8)    4-[5-Phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (9)    4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (10)    4-[5-(4-Trifluoromethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (11)    4-[5-(2-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (12)    4-[5-(4-Chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (13)    4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-carboxylate-   (14)    4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazol-3-carboxamide-   (15)    4-[5-(4-[Methylthio]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (16)    4-[5-(4-[Methylsulfonyl]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (17)    4-[5-(2,4-[Difluoro]phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (18)    4-[5-(2,6-[Difluoro]phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (19)    4-[5-(4-Cyanophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (20)    4-[5-(4-Chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (21)    4-[5-(4-Chlorophenyl)-3-(chloro-difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (22)    4-[5-(4-Chlorophenyl)-3-(pentafluoroethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (23)    4-[5-(4-Biphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (24)    4-[5-(4-Pyrazinyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (25)    4-[5-(5-Chloro-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (26)    4-[5-(4-Morpholino)phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (27)    4-[5-(1-Cyclohexyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (28)    4-[5-(5-Bromo-2-thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (29)    4-[5-(4-Thienyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (30)    4-[5-(4-[Trifluoromethyl]phenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (31)    4-[5-(3,4-Dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (32)    4-[5-(2,4-Dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (33)    4-[5-Phenyl-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (34)    4-[5-(4-Fluorophenyl)-3-(3-hydroxypropyl)-1H-pyrazol-1-yl]benzenesulfonamide-   (35) 4-[4-(Aminosulfonyl)phenyl]-5-(4-fluorophenyl)    1H-pyrazole]-3-propanoic acid-   (36)    4,5-Dihydro-4-[3-trifluoromethyl]-1H-benz[g]indazol-1-yl]benzenesulfonamide-   (37)    4-[5-(4-Chlorophenyl)-4-chloro-1H-pyrazol-1-yl]benzenesulfonamide-   (38)    4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-4-chloro-1H-pyrazol-1-yl]benzenesulfonamide-   (39)    4-[1-(4-Fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide-   (40) 1-(2,4,6-Trichlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetic    acid-   (41) 1-(2,6-dichlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetic    acid-   (42)    3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-hydroxy-2-propyl)thiophene-   (43) 3-(4-(Aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene-   (44) 3-(4-(Amino    sulfonyl)phenyl)-2-(4-fluorophenyl)-5-(2-propyl)thiophene-   (45) 3-(4-(Aminosulfonyl)phenyl)-2-cyclohexylthiophene-   (46)    5-(4-Carboxyphenyl)-4-(4-(methylsulfonyl)phenyl)thiophene-2-carboxylic    acid-   (47)    4-(4-Fluorophenyl)-2-methyl-5-(4-(methylsulfonyl)phenyl)thiazole-   (48)    2-(4-Fluorophenyl)-3-(4-methylsulfonyl)phenyl)-2-cyclopenten-1-one-   (49) 4-(4-(Methylsulfonyl)phenyl-5-(4-fluorophenyl)-isothiazole-   (50) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl-2-(5H)-furanone-   (51) 3-(4-Fluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone-   (52) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-furanone-   (53)    5,5-Dimethyl-3-(4-fluorophenyl)-4-(4-methylsulfonyl-phenyl)-2-(5H)-furanone-   (54) 2-((4-Aminosulfonyl)phenyl)-3-(4-fluorophenyl)thiophene-   (55)    3-(2,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (56)    3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (57)    3-(2,6-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (58)    3-(2,5-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (59)    3-(3,5-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (60) 3-(4-Bromophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (61) 3-(4-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (62)    3-(4-Methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (63) 3-(Phenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (64) 3-(2-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (65)    3-(2-Bromo-4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (66)    3-(2-Bromo-4-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (67) 3-(4-Chloro-2-fluorophenyl)-4-(4-(methylsulfonyl)    phenyl)-2-(5H)-furanone-   (68)    3-(3-Bromo-4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (69) 3-(3-Chlorophenyl)-4-(4-(methylsulfonyl)    phenyl)-2-(5H)-furanone-   (70) 3-(2-Chloro-4-fluorophenyl)-4-(4-(methylsulfonyl)    phenyl)-2-(5H)-furanone-   (71)    3-(2,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (72)    3-(3,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (73)    3-(2,6-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (74)    3-(3-Chloro-4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (75)    3-(4-Trifluoromethylphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (76)    3-(3-Fluoro-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (77)    3-(3-Chloro-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (78)    3-(3-Bromo-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (79) 3-(2-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (80)    3-(4-Methylthiophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (81) 3-(3-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H-furanone-   (82)    3-(2-Chloro-6-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (83)    3-(3-Bromo-4-methylphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (84)    3-(4-Bromo-2-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (85)    3-(3,4-Dibromophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (86)    3-(4-Chloro-3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (87)    3-(4-Bromo-3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (88)    3-(4-Bromo-2-chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (89) 3-(2-Naphthyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (90) 3-(7-Quinolinyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone-   (91)    3-(3,4-Dichlorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone-   (92)    3-(3,4-Dichlorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone-   (93)    3-(3,4-Dichlorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone-   (94)    3-(3-Bromo-4-methoxyphenyl)-4-(4-(aminosulfonyl)phenyl)-2-(2H)-furanone-   (95) 3-(4-(Methylsulfonyl)phenyl)-2-phenylbenzo[b]furan-   (96) 3-(4-Methylsulfonyl)phenyl)-2-phenylbenzo[b]thiophene-   (97) 3-(4-Methylsulfonyl)phenyl-2-phenylinden-1-one-   (98) 2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)indole-   (99) 3-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)indole-   (100)    2-(4-Fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-4H-thieno[2,3-c]-furan-6-one-   (101)    2-(3,4-Difluorophenyl)-3-(4-(methylsulfonyl)phenyl)-4H-thieno[2,3-c]-furan-6-one-   (102)    2-(4-Fluorophenyl)-3-(4-(aminosulfonyl)phenyl)-4H-thieno[2,3-c]-furan-6-one-   (103)    2-(3,4-Difluorophenyl)-3-(4-(aminosulfonyl)phenyl)-4H-thieno[2,3-c]-furan-6-one-   (104)    3-(4-(Methylsulfonyl)phenyl)-2-phenyl)-4,7-dihydrothieno[2,3-c]pyran-5-one-   (105)    2-(4-(Methylsulfonyl)phenyl)-3-phenyl)-4H-thieno[2,3-c]furan-6-one-   (106) 5-(4-(Methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole-   (107)    2-Methyl-5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole-   (108)    3-Methyl-5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole-   (109)    2-Bromo-5-(4-(methylsulfonylphenyl)-6-phenylimidazo[2,1-b]thiazole-   (110)    3-Trifluoromethyl-5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole-   (111)    2,3-Dimethyl-5-(4-(methylsulfonyl)phenyl)-6-phenyl-imidazo[2,1-b]thiazole-   (112) 5-(4-(Methylsulfonyl)phenyl)-6-(4-fluorophenyl)    imidazo[2,1-b]thiazole-   (113) 5-Phenyl)-6-(4-(methylsulfonyl)phenyl)-imidazo[2,1-b]thiazole-   (114)    2-Chloro-5-(4-(methylsulfonyl)phenyl)-6-(4-chlorophen-yl)imidazo[2,1-b]thiazole-   (115)    2,2-Dichloro-5-(4-(methylsulfonyl)phenyl)-6-(4-chlorophenyl)imidazo[2,1-b]thiazole-   (116)    5-(4-(Methylsulfonyl)phenyl)-6-(imidazo[2,1-b]-1,3,4-thiadiazole-   (117)    5-Phenyl-6-(4-(methylsulfonyl)phenyl)-imidazo[2,1-b]-1,3,4-thiadiazole-   (118)    2-Methyl-5-(4-(methylsulfonyl)phenyl)-6-phenyl-imidazo[2,1-b]-1,3,4-thiadiazole-   (119)    2-Methyl-5-phenyl-6-(4-methylsulfonyl)phenyl)-imidazo[2,1-b]-1,3,4-thiadiazole-   (120)    5-(4-(Methylsulfonyl)phenyl)-6-(4-fluorophenyl)-imidazo[2,1-b]-1,3,4-thiadiazole-   (121)    5-(4-(Methylsulfonyl)phenyl)-6-phenyl-1H-imidazo[2,1-b]-s-triazole-   (122)    5-Phenyl-6-(4-(methylsulfonyl)phenyl)thiazolo[3,2-b]-1,3,4-triazole-   (123)    2,3-Dihydro-5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo[2,1-b]thiazole-   (124) 2-[(4-Methylthio)phenyl]-1-biphenyl-   (125) 1-Cyclohexene-2-(4′-methylsulfonylphenyl)benzene-   (126) 3-(4′-Methylsulfonylphenyl)-4-phenylphenol-   (127) 1-[2-(4-Methylsulfonylphenyl)phenyl]piperidine-   (128) 1-[2-(4′-Methylsulfonylphenyl)phenyl]pyrrole-   (129) 1-Phenoxy-2-(4′-methylsulfonylphenyl)benzene-   (130)    5-(4-Fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine-   (131)    2-Ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine-   (132)    5-(4-Fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6-(trifluoromethyl)pyridine-   (133)    2-Bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine-   (134) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]propanoic    acid-   (135) 3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]butanoic    acid, sodium salt-   (136)    2-Benzyl-3-[1-(p-bromobenzyl)-5-methoxy-2-methylindol-3-yl-propanoic    acid-   (137)    3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2,2-dimethylpropanoic    acid-   (138)    3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-4,4,4-trifluorobutanoic    acid, sodium salt-   (139) trans-2-[1-(p-Bromobenzyl    5-methoxy-2-methylindol-3-yl]-cyclo-propanecarboxylic acid, sodium    salt-   (140)    3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-hydroxy-2-methyl    propanoic acid, sodium salt-   (141)    [1-(1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-cyclopropylacetic    acid, sodium salt-   (142)    trans-(+)-2-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]cyclopropanecarboxylic    acid, sodium salt-   (143)    3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2-methylpropanoic    acid and sodium salt-   (144)    3-[1-(p-Chlorobenzyl)-5-methoxy-2-methylindol-3-yl]-4,4,4-trifluorobutanoic    acid and sodium salt-   (145)    syn-3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2-methylbutanoic    acid-   (146)    anti-3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2-methylbutanoic    acid and sodium salt-   (147) 3-[5-(Bromo-1-(p-bromobenzyl)-2-methylindol-3-yl]butanoic acid    and sodium salt-   (148)    (−)-3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-butanoic acid    and sodium salt-   (149)    (+)-3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-butanoic acid    and sodium salt-   (150)    trans-(−)-2-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]cyclopropanecarboxylic    acid and sodium salt-   (151) 3-[1-(p-Bromobenzyl)-2,5-dimethylindol-3-yl]propanoic acid-   (152) 3-[5-(Bromo-1-(p-bromobenzyl)-2-methylindol-3-yl]propanoic    acid-   (153) 3-[1-(p-Bromobenzyl)-5-chloro-2-methylindol-3-yl)propanoic    acid-   (154)    3-[1-(p-Chlorobenzyl)-5-methoxy-2-methylindol-3-yl)-2-methylpropanoic    acid-   (155) Methyl    3-[1-(p-bromobenzyl)-5-methoxy-2-methylindol-3-yl)propanoate-   (156)    3-[1-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl)-3-methylbutanoic    acid-   (157) 5-Methanesulfonamido-6-(2,4-difluorophenylthio)-1-indanone-   (158) 5-Methanesulfonamido-6-(2,4-dichlorophenoxy)-1-indanone-   (159)    2-(4-Chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole-   (160)    2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole-   (161)    1-(4-Fluorophenyl)-4-hydroxy-2-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole-   (162)    1-(4-Fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole-   (163)    2-(4-Chlorophenyl)-1-[4-methylsulfonyl)phenyl]-4-methyl-1H-imidazole-   (164)    2-(4-Chlorophenyl)-1-[4-methylsulfonyl)phenyl]-4-phenyl-1H-imidazole-   (165)    2-(4-Chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-   (166)    4-(4-Bromophenyl)-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-   (167)    2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(2-naphthyl)-1H-imidazole-   (168)    2-(4-Chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-[4-(trifluoromethoxy)phenyl]-1H-imidazole-   (169)    2,4-Bis(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-   (170)    2-(4-Chlorophenyl)-4-(3-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-   (171)    2-(4-Chlorophenyl)-4-(4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-   (172)    2-(4-Chlorophenyl)-4-(3-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-   (173)    2-(4-Chlorophenyl)-4-[(4-chlorophenoxy)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-   (174)    2-(3-Chloro-4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole-   (175)    5-[1-[4-(Methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imidazole-2-yl]-1,3-benzodioxole-   (176)    2-(3-Fluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)-phenyl-4-(trifluoromethyl)-1H-imidazole-   (177)    2-(4-Chlorophenyl)-4-[(phenylthio)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-   (178)    2-(4-Chlorophenyl)-4-[(N-methyl-N-phenylamino)methyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-   (179)    2-(4-Chlorophenyl)-4-[2-quinolyl)methoxymethyl]-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-   (180)    2-(4-Chlorophenyl)-4-methoxymethyl-1-[4-(methylsulfonyl)phenyl]-1H-imidazole-   (181)    2-(4-Fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole-   (182)    1-[4-(Methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1H-imidazole-   (183)    2-(3-Chloro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole-   (184)    2-(4-Methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole-   (185)    1-[4-(Methylsulfonyl)phenyl]-2-(4-trifluoromethyl-phenyl)-4-trifluomethyl-1H-imidazole-   (186)    4-[2-(4-Chlorophenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide-   (187)    4-[2-(3-Chloro-4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide-   (188)    3-[1-(4-Methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine-   (189)    2-[1-(4-Methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine-   (190)    4-[1-[4-(Methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine-   (191)    2-Methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine-   (192)    2-Methyl-6-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine-   (193)    5-Methyl-2-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine-   (194)    4-Methyl-2-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine-   (195)    2-Methoxy-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine-   (196)    4-[2-(6-Methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide-   (197)    4-[2-(6-Methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide-   (198)    3-Methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine-   (199)    4-[2-(4-Methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide-   (200)    2-[1-[4-(Methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]thiophene-   (201)    3-[1-[4-(Methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]thiophene-   (202)    4-[2-(5-Methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide-   (203)    2-Methyl-3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]thiophene-   (204)    4-[2-(2-Methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide-   (205)    4-[2-Pyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide

The synthesis of compounds 1–39 is disclosed in Talley et al. U.S. Pat.No. 5,466,823. The synthesis of compounds 40 and 41 is disclosed inBlack et al. U.S. Pat. No. 5,436,265. The synthesis of compounds 42–94is disclosed in Ducharme et al. U.S. Pat. No. 5,474,995. The synthesisof compounds 95–105 is disclosed in Prasit et al. U.S. Pat. No.5,521,213. The synthesis of compounds 106–123 is disclosed in Gauthieret al. U.S. Pat. No. 5,552,422. The synthesis of compounds 124–129 isdisclosed in Batt U.S. Pat. No. 5,593,994. The synthesis of compounds130–133 is disclosed in Lee U.S. Pat. No. 5,596,008. The synthesis ofcompounds 134–156 is disclosed in Lau et al. U.S. Pat. No. 5,604,253.The synthesis of compounds 157 and 158 is disclosed in Guay et al. U.S.Pat. No. 5,604,260. The synthesis of compounds 159–205 is disclosed inKhanna et al. U.S. Pat. No. 5,616,601.

Other selective inhibitors of cyclooxygenase-2 and their synthesis aretaught in Examples 2–108, 110–129, 131–150, 152, 301–312, and 401–413 ofBatt et al. U.S. Pat. No. 5,593,994, the disclosure of which isincorporated herein by reference. Still other selective inhibitors ofcyclooxygenase-2 and their synthesis are taught in Examples 1–11, 13–16,and 18–25 of Guay et al. U.S. Pat. No. 5,604,260, the disclosure ofwhich is incorporated herein by reference. Still other selectiveinhibitors of cyclooxygenase-2 and their synthesis are taught inExamples 1–13 including Examples 1a–1p and 4a–4h of Talley et al. U.S.Pat. No. 5,633,272, the disclosure of which is incorporated herein byreference. Still other selective inhibitors of cyclooxygenase-2 aretaught in Examples 1–131 of Lau et al. U.S. Pat. No. 5,639,780, thedisclosure of which is incorporated herein by reference. Still otherselective inhibitors of cyclooxygenase-2 are taught in Examples 1–6 ofTalley et al. U.S. Pat. No. 5,643,933, the disclosure of which isincorporated herein by reference. Still other selective inhibitors ofcyclooxygenase-2 are taught in Examples 1–4 of Lau et al. U.S. Pat. No.5,510,368, the disclosure of which is incorporated herein by reference.

Preferred inhibitors of cyclooxygenase-2 for use herein are4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamidewhich is compound (1) set forth above and4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamidewhich is compound (4) set forth above; it is believed the lattercompound is celicoxib (Trade name Celebrex). Another preferred selectiveinhibitor of cyclooxygenase-2 is vioxx which is MK-0966. Other preferredinhibitors of cyclooxygenase-2 for use in this embodiment are thosedescribed hereinafter in connection with the third embodiment herein.

The dosage of inhibitor of cyclooxygenase-2 for the method of the firstembodiment herein is a cyclooxygenase-2 inhibiting amount which is atherapeutically effective amount. In general, the dosage for the firstembodiment herein ranges from 0.1 to 30 mg/kg. The dosages for anyparticular agent will vary within said range. For compound (1) referredto above, the dosage preferably ranges from 3 to 12 mg/kg. Theadministration is preferably chronic treatment, i.e., carried outindefinitely.

The route of administration for the inhibitors of cyclooxygenase-2 forthe first embodiment herein is preferably oral but other routes ofadministration, e.g., parenteral such as intravenous, are also useful.

We turn now to the second embodiment herein, which is a method oftreating a patient with a virus-caused liver disease with acyclooxygenase-2 inhibiting amount of a selective inhibitor ofcyclooxygenase-2 and a therapeutic amount of an anti-viral drug wherethe cyclooxygenase-2 inhibitor is an adjunct to the anti-viral therapyto increase the effectiveness thereof.

For the second embodiment herein, the virus-cause liver diseasesinclude, for example, chronic viral hepatitis B and chronic viralhepatitis C.

For the second embodiment herein, the inhibitors of cyclooxygenase-2that are useful are the same as those for the first embodiment hereinand the dosage regimen and routes of administration are the same as forthe first embodiment.

The anti-viral drugs are the same as those used conventionally for thedisorder treated, and the dosages and routes of administration are thoseconventional for the disorder treated. For example, for chronichepatitis B, various interferons, e.g., recombinant and natural alphainterferons, are administered parenterally and for chronic hepatitis C,interferon alpha-2b is administered subcutaneously (3 MU three times aweek for six months). Other anti-viral compounds for use in the secondembodiment herein include, for example, acyclovir, adenine arabinoside,and ribavirin, used, for example in conventional dosages. Combinationsof agents, e.g., a combination of interferon and ribavirin, may be usedwith the selective inhibitor of cyclooxygenase-2.

We turn now to the third embodiment herein which is directed toselective inhibitors of cyclooxygenase-2 which directly inhibit theenzyme cyclooxygenase-2 and which also inhibit the synthesis ofcyclooxygenase-2 protein and which have antioxidant properties.

The cyclooxygenase-2 inhibitors for this third embodiment preferablycontain phenyl group with two or more substituents selected from thegroup consisting of hydroxy and C₁₋₄-alkoxy (e.g., methoxy) on thephenyl. Such compounds are embraced by generic description in variouspatents but no species of selective cyclooxygenase-2 inhibitorcontaining phenyl group with two or more hydroxy or alkoxy substituentsis disclosed in any of said patents. The patents referred to are: Talleyet al. U.S. Pat. No. 5,643,933; Talley et al. U.S. Pat. No. 5,633,272;Khanna et at U.S. Pat. No. 5,616,601; Lee U.S. Pat. No. 5,596,008; Battet al. U.S. Pat. No. 5,593,994; and Adams et al. U.S. Pat. No.5,593,992.

Specific compounds for the third embodiment herein include, for example,4-[5-methyl-3-[[(2,3-hydroxy)phenoxy]methyl]-1H-pyrazol-1-yl]benzenesulfonamideand4-methyl-5-(4-methylsulfonyl)phenyl-2-[(2,3-hydroxyphenoxy)methyl]oxazoleand the corresponding compounds where methoxy or ethoxy replaceshydroxy.4-[5-Methyl-3-[[(2,3-hydroxy)phenoxy]methyl]-1H-pyrazol-1-yl]benzenesulfonamidehas the structure

where R¹ is methyl and R₂ is NH₂.4-(Methyl)-5-(4-methylsulfonyl)phenyl-2-[(2,3-hydroxyphenoxy)methyl]oxazolehas the structure

These compounds are embraced by broad disclosure in Talley et al. U.S.Pat. No. 5,643,933 but are not specifically disclosed therein. Thesecompounds can be made analogously to Scheme XXII in U.S. Pat. No.5,643,933 by reacting 2,3-dihydroxybenzyl bromide, where the hydroxygroups are protected by conventional techniques (for example, asdescribed in E. Haslam, “Protection of Phenols and Catechols”, pages145–182 in Protective Groups in Organic Chemistry, McOmie, J. F. W.,editor, Plenum Press, London (1973), with alcohol corresponding to theproduct sought, in the presence of base, and deprotecting, and in thecase of the methoxy or ethoxy compounds with alkoxy substituents inphenyl moiety, replacing the hydroxy substituents with alkoxy.Alternatively, these compounds can be made by reacting said alcohol withmesyl chloride to yield the unstable mesylate and then reacting withappropriate trihydroxyphenol. These compounds directly inhibit thecyclooxygenase-2 enzyme and also inhibit the synthesis ofcyclooxygenase-2.

The selective inhibitors of cyclooxygenase-2 for the third embodimentherein have utility as broad spectrum anti-inflammatory agents fortreating inflammation and inflammation-associated disorders mediated bycyclooxygenase-2 such as arthritis, inflammatory bowel disease,diabetes, Alzheimer's disease, pancreatitis, inflammatory vascular andocular disorders, and liver disease (as described in conjunction withthe first embodiment herein). They also have utility in preventing ortreating cancer. The dosages are generally those set forth for selectiveinhibitors of cyclooxygenase-2 in the first embodiment herein. The routeof administration is preferably oral although other routes ofadministration, e.g., parenteral, such as intravenous, may also be used.

The selective inhibitors of cyclooxygenase-2 of the third embodimentherein have improved anti-inflammatory efficacy compared to selectiveinhibitors of cyclooxygenase-2 which do not inhibit the synthesis ofcyclooxygenase-2 protein.

The three embodiments described above are illustrated in the followingexamples.

EXAMPLE I

A patient with alcoholic hepatitis is admitted to a hospital complainingof nausea and upper abdominal pain. Liver function test results aretotal bilirubin of 4.0 mg/dl, direct bilirubin of 3.1 mg/dl, ALT of 100IU/L, AST of 120 IU/L and prothrombin time of 15.1 seconds.

Treatment is carried out by administration of4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamideat a dosage of 6 mg/kg by oral route of administration, daily.

At the end of three weeks, the nausea and upper abdominal pain haveresolved. Each of the blood tests has improved.

The same result is obtained when the drug administered is4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamideat a dosage of 6 mg/kg by oral route of administration daily.

EXAMPLE II

The patient is a 45-year old female with new onset nausea, loss ofappetite and right upper quadrant tenderness. She is noted to haveelevated liver chemistries. Serologic workup is notable for positiveantinuclear and antismooth muscle antibodies. She is considered to haveautoimmune hepatitis. Liver biopsy is consistent with this diagnosis.Treatments with 6 mg/kg oral4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene-sulfonamidefor two months, results in resolution of symptoms. The patient issubsequently maintained on an oral dose of 6 mg/kg of the same drug.

The same result is obtained when the drug administered is4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamideat an oral dose of 6 mg/kg.

EXAMPLE III

A patient having symptoms of malaise, anorexia and fatigue, haspersistently elevated liver function tests. A blood test confirms thediagnosis of chronic viral hepatitis C.

The patient is treated by oral administration of4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene-sulfonamideat a dose of 6 mg/kg, daily for 12 months and also with subcutaneousinterferon alpha-2b at a dose of 3 MU three times a week for six months,resulting in sustained normalization of liver enzymes.

The same result is obtained when the cyclooxygenase-2 inhibitor is4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamideat an oral dose of 6 mg/kg and the anti-viral drug is subcutaneousinterferon alpha-2b at a dose of 3 Mu three times a week for six months.

EXAMPLE IV

where R¹ is methyl and R² is NH₂ is reacted with2,3-dihydroxybenzylbromide where the hydroxyls are protected, underbasic conditions (K₂CO₃), and then deprotecting is carried out toproduce4-[5-methyl-3-[(2,3-hydroxy)phenoxy]methyl]-1H-pyrazol-1-yl]benzenesulfonamide.The product has the structure

where R¹ is methyl and R² is NH₂. The starting material is made by thereaction to produce compound 78 in Scheme XVII depicted in Talley et al.U.S. Pat. No. 5,643,933.

Many variations of the above will be obvious to those skilled in theart. Thus, the invention is defined by the claims.

1. A method of treating a patient affected with liver disease selectedfrom the group consisting of chronic viral hepatitis B, chronic viralhepatitis C, alcoholic liver injury and nonalcoholic steatohepatitis,comprising administering to said patient a cyclooxygenase-2 inhibitingamount of a selective inhibitor of cyclooxygenase-2.
 2. The method ofclaim 1, wherein the selective inhibitor of cyclooxygenase-2 is4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.3. The method of claim 1, wherein the selective inhibitor ofcyclooxygenase-2 is4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide.4. The method of claim 1 wherein the selective inhibitor ofcyclooxygenase-2 directly inhibits the enzyme cyclooxygenase-2 and alsoinhibits the synthesis of cyclooxygenase-2 protein and contains phenylgroup with two or more substituents selected from the group consistingof hydroxy and C₁₋₄-alkoxy on the phenyl group.